Process for the preparation of 2-(2-aminoethyl)isoindolines



United States Patent 3,466,298 PROCESS FOR THE PREPARATION OF 2-(2-AMINOETHYL)ISOINDOLINES Theodore S. Sulkowski, Narberth, and Albert A. Mascitti, Norristown, Pa., assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Mar. 14, 1967, Ser. No. 622,928 Int. Cl. C07d 27/48 US. Cl. 260-326.1

ABSTRACT OF THE DISCLOSURE This invention is concerned with a process for the preparation of 2-(2-aminoethyl)isoindolines which are pharmacologically efficacious as antidepressants and anorexiants. This process involves the substitution of a 2-(2- aminoethyl)-3-hydroxyphthalimidine with a halogen to afford a Z-(Z-aminoethyl)-3-halophthalimidine which by a displacement reaction i converted to a 3-alkoxy-2-(2- aminoethyl)phthalimidine which is then subjected to hydrogenolysis to yield a 2-(2-aminoethyl)isoindoline.

This invention relates to a new and novel process for the preparation of 2-(2-aminoethyl)isoindolines which are known to possess pharmacological activity and are useful as antidepressants and anorexiants.

The new and novel process of the present invention is exemplified by the following reaction scheme:

0 II R2 \W\NGHECH2NH2 Substitution l R/\/ ["OH ii R2 H N-cmonmm R4 R I l Displacement 5? R2 I-Iydrogenolysis N-omonsNnz 3 R1 (III) N-CH2C1I2NH2 3 R. (IV) wherein R is selected from the group consisting of hydrogen, lower alkyl, phenyl, phen(lower)alkyl, monohalophenyl, dihalophenyl, mono(lower) alkylphenyl, di- (lower)alkylphenyl, trifluoromethylphenyl, mono(lower) alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, furyl and tetrahydro-Z-naphthyl; R is selected from the group consisting of hydrogen, amino, lower alkylamino, halogen, lower alkyl and lower alkoxy; R is hydrogen when R and R are dissimilar and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is selected from the group consisting of chloro and bromo; and R is lower alkoxy. Typical compounds prepared by this process are 2-(2-aminoethyl)-1-(4-chlorophenyl) 7 Claims "ice isoindoline hydrochloride; Z-(Z-aminoethyl)-1-(3,4-dichlo rophenyl) isoindoline and 2 (Z-aminoethyl) -1-phenylisoindolin hydrochloride.

The substitution reaction is effected by contacting a 2-(2-aminoethyl)-3-hydroxyphthalimidine (I) with a halogenating reagent at a temperature range from about 25 C. to about 50 C. for a period of about one-half hour to about three hours. Preferably this reaction is conducted with thionyl chloride at the reflux temperature of the reaction mixture for about one hour. When the substitution reaction is complete, the 2-(2-aminoethyl)-3-halophth-alimidine (II) may be separated by conventional recovery procedures, eg, concentration and recrystallization. Alternatively, the 2-(2-aminoethyl)-3-halophthalimidine (II) may be merely isolated by concentration and then used directly in the following reaction.

The displacement reaction is conducted by dissolving the above prepared Z-(Z-aminoethyl)-3-halophthalimidine (II) in an alkanol and heating the: resulting mixture at a temperature range from about 25 C. to about C. for a period of about one-half hour to about three hours. Preferably this reaction is conducted in ethanol at the reflux temperature of the reaction mixture for a period of about one hour. When the displacement reaction is complete, the resulting 3alkoxy-2-(2-aminoethyl)phthalimidine (III) is obtained by standard recovery means, such as, concentration; reconstitution in a mixture of a water immiscible solvent and an alkali metal hydroxide, carbonate or bicarbonate solution, e.g. ethyl acetate-aqueous sodium carbonate solution, tolueneaqueous sodium hydroxide; and reconcentration.

The hydrogenolysis of the above prepared 3-alkoxy-2- (Z-aminoethyl) phthalimidine (III) is accomplished by contact with lithium aluminum hydride in ,an anhydrous reaction-inert organic solvent, at a temperature range of about 35 C. to about C. for a period of about two to twenty hours. Preferably this reaction is conducted in ether at about the reflux temperature of the reaction mixture for a period of about seventeen hours.

When the hydrogenolysis reaction is complete, the product is recovered by procedures well known in the art, for example, the excess lithium aluminum hydride is decomposed by the addition of water, the organic layer is separated, dried over a desiccant and then evaporated to dryness to afford a 2-(Z-aminoethyl)isoindoline (IV).

Since many of the compounds prepared by the process of the present invention are basic, advantage may be taken of the water solubility of salts of these compounds formed with acids in the isolation and/or purification of the above compounds and in the preparation of aqueous solutions of these compounds for oral parenteral administration. Of course, only salts formed with pharmaceutically acceptable acids should be employed in therapeutic applications. Particularly effective salts are those formed with pharmaceutically acceptable acids having a pK value of 3 or lower. Such acids are well known in the art, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, benzenesulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic acids and the like. These salts may be prepared by pro cedures commonly employed in the :art, for example, reacting the compounds with an equivalent of the selected acid in aqueous solution and concentration of the solution. Other known procedures may also be employed.

The time and temperature ranges employed in the aforesaid reactions are not critical but simply represent the most convenient range consistent with carrying out these reactions in a minimum of time without undue difllculty. Thus, reaction temperatures appreciably below these can be used, but their use considerably extends the reaction time' Similarly, reaction temperatures higher than those mentioned can be employed with a concomitant decrease in reaction time. By the term halogenating reagent as employed herein is meant a reagent capable of replacing the 3-hydroxy moiety of a 2-(2aminoethyl)-3-hydroxyphthalimidine with a chlorine or bromine atom, examples of such reagents are: phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and thionyl chloride. When the substitution reaction is conducted with a nonliquid halogenating reagent, such as phosphorus pentachloride, a solvent, e.g. benzene, should be employed to dissolve the reactants. The term anhydrous reaction-inert organic solvent includes any water-free organic solvent which will dissolve the 3-alkoxy-2-(2-aminoethyl)phthalimidine (III) but will not interfere with the hydride reduction thereof. Many such solvents are well known to those skilled in the art of organic chemistry, examples are: ethyl ether, diisopropyl ether, tetrahydrofuran, dioxan, diethylene glycol dimethyl and ether and ethylene glycol dimethyl ether.

The 2-(2-aminoethyl)-3-hydroxyphthalimidines which are used as starting materials in the process of the present invention are known compounds which may be prepared by procedures well known in the art, for example, the condensation of an acid chloride of a benzoyl benzoic acid with an ethylene diamine in pyridine. Alternatively, the 2-(2-aminoethyl)-3-hydroxyphthalimidines are also prepared by the procedure disclosed and claimed in copending and cofiled US. patent application, Ser. No. 622,918, entitled Tetrahydropyrimidinyl Phenyl Carbonyl and Imidazolinyl Phenyl Carbonyl Compounds which is a continuation-in-part application of United States patent application, Ser. No. 576,833, filed on Sept. 2, 1966, and now abandoned.

The new and novel process of the present invention is utilized to prepare 2-(2-aminoethyl)isoindolines (IV) which are known to possess pharmacological activity and are useful as antidepressants and anorexiants. These 2-(2- aminoethyl)isoindolines are described and claimed in US. patent application Ser. No. 622,917, filed on Mar. 14, 1967, entitled Isoindoles, Isoindolines and Related Compound which is also a continuation-in-part application of the above US. patent application, Ser. No. 576,833, filed on Sept. 2, 1966, and now abandoned.

The following examples are given by way of illustration.

EXAMPLE I Twenty grams of 2-(2-aminoethyl)'3-(4-chlorophenyl)- 3-hydroxyph-thalimidine hydrochloride and 25 ml. of thionyl chloride are refluxed for one hour. The mixture is evaporated to dryness and the residue admixed with absolute ethanol (50 ml.) which is then refluxed one hour. Thereafter, the mixture is evaporated to dryness and the residue is shaken with an ethyl acetate and sodium carbonate solution. The ethyl acetate layer is dried over magnesium sulfate, then evaporated to dryness to afford 2 (2 aminoethyl) 3-(4-chlorophenyl)-3-ethoxyphthalimidine, M.P. 118120 C.

Thirteen grams of the above prepared phthalimidine are added in portions to a stirred suspension of 2.5 g. of lithium aluminum hydride in 350 ml. of anhydrous ether. After refluxing for seventeen hours, the mixture is decomposed by careful addition of water. The ether layer is dried over magnesium sulfate, then saturated with anhydrous hydrogen chloride and the resulting solid is separated and recrystallized from ethanol-ether. On drying there is obtained 2-(2-aminoethyl)-1(4-chlorophenyl)isoindoline hydrochloride, M.P. 220-223 C.

Analysis.-for c H N Cl. Calcd: C, 62.15; H, 5.87; N, 9.06; Cl, 22.93. Found: C, 61.76; H, 6.09; N, 9.44; Cl, 22.70.

In a similar manner, the above substitution reaction is conducted with phosphorus pentachloride in ether.

EXAMPLE II Forty grams of Z-(Z-aminoethyl)-3-hydroxy-3-phenylphthalimidine hydrochloride and 50 ml. of thionyl chloride are refluxed for two hours. The mixture is evaporated to dryness, admixed with absolute ethanol ml.) and refluxed for two hours. Subsequently, the mixture is evaporated to dryness and the residue shaken with ethyl acetate and sodium bicarbonate solution. The ethyl acetate layer is dried over magnesium sulfate then evaporated to dryness to obtain 2-(2-aminoethyl)-3-ethoxy-3-phenylphthalimidine.

Twenty-six grams of the above phthalimidine are added in portions to a stirred suspension of 5.0 g. of lithium aluminum hydride in 700 ml. of anhydrous ether. After refluxing for ten hours, the mixture is decomposed by careful addition of water. The ether layer is dried over magnesium sulfate and then saturated with anhydrous hydrogen chloride. The soid is separated, recrystallized from ethanolether and dried to afford 2-(2-aminoethyl)- l-phenylisoindoline hydrochloride.

EXAMPLE III Ten grams of 2-(2-aminoethyl)-6-bromo-3-hydroxy-3- (4-tolyl)phthalimidine and 12.5 ml. of thionyl chloride are stirred at 25 C. for two hours. Thereafter, the reaction mixture is evaporated to dryness to afford 2-(2-aminoethyl -6-bromo-3-chloro-3- 4-tolyl phthalimidine.

The above prepared 2-(2-aminoethyl)-6-bromo-3-choro-3-(4-tolyl)phthalimidine is admixed with methanol (25 ml.) and stirred at room temperature for two hours. Subsequently, the reaction mixture is evaporated to dryness and the residue shaken with a mixture of ether and aqueous sodium hydroxide. The organic layer is dried over magnesium sulfate and then evaporated to dryness to yield 2-(2-aminoethyl)-6-bromo3-methoxy-3-(4-tolyl) phthalimidine.

The above prepared 2-(2-aminoethyl)-6-bromo-3-methoxy-3-(4-tolyl)phthalimidine (6 g.) is added in portions to a stirred suspension of 1.5 g. of lithium auminum hydride in ml. of anhydrous dioxan. After heating the resulting mixture for fifteen hours at 50 C., the mixture is decomposed by careful addition of water. The organic layer is dried over magnesium sulfate and evaporated to dryness to afford 2-(2-aminoethyl)-5-bromo-1-(4-tolyl) isoindoline.

The above process is repeated starting with 2-(2-aminoethyl)-3-hydroxy-5-methyl-3-propylphthalin1idine to afford 2-(2-aminoethyl -6-methyl-l-propylisoindoline.

EXAMPLE IV Five grams of 2-(2 aminoethyl)-5,6-dibromo-3-(4- bromophenyl)-3-hydroxyphthalimidine and 7 ml. of phosphOrus tribromide are heated to 50 C. for one-half hour. Thereafter, the reaction mixture is evaporated to dryness to afford 2-(2-aminoethyl)-3,5,6-tribromo-3-(4-bromophenyl)phthalimidine The above prepared phthalimidine is admixed with propanol (25 ml.) and the mixture is refluxed for onehalf hour. Subsequently, the reaction mixture is evaporated to dryness and the residue shaken with ether and aqueous potassium carbonate. The organic layer is dried over magnesium sulfate and then evaporated to dryness to yield Z-(Z-aminoethyl)-5,6-dibromo-3-(4-bromophenyl)- 3-propoxy-phthalimidine.

The above prepared phthalimidine (2 g.) is added in portions to a stirred suspension of 0.5 g. of lithium aluminum hydride in 60 ml. of anhydrous tetrahydrofuran. After heating the resu ting mixture at reflux temperatures for twenty hours, the mixture is decomposed by careful addition of water. The organic layer is dried over magnesium sulfate and evaporated to dryness to afford 2-(2- aminoethyl -5,6-dibromo-1- (4-bromophenyl isoindoline.

In a similar manner, the above procedure is repeated to afford 2-(Z-aminoethyl)-7-iodoisoind0line and 2-(2-aminoethyl)-1-(3,4-dichlorophenyl)isoindoline.

5 i 6 EXAMPLE'V to afford 2-(2-aminoethyl)-3-chloro-6-ethylamino-3- phenylphthalimidine. Twenty grams of 2-( Y P The above prepared phthalimidine is admixed with X Y yP and 25 Of thiohyl h' ethanol (25 ml.) and the mixture heated to reflux temrlde are refluxed for One hour- Thereafter, the reaehon perature for one hour. Subsequently, the reaction mixture mixture is evaporated to dryness to afford 2- (2- is evaporated to dryness and the residue shaken with ethyl y P y1)phthalrmidme. acetate and aqueous sodium bicarbonate. The organic The above pr p y r layer is dried over magnesium sulfate and then evaporated dichlorophenyl)phthalimidine is admixed with ethanol t dryness to i ld 2-(2- j h 1)-3 h 1 (50 ml.) and the mixture heated to thereflux temperature 10 amino-3-phenylphthalimidine,

of the reaction mixture for one hour. Subsequently, the The above prepared phthalimidine (10 g.) is added in reaction mixture is evaporated to dryness and the residue portions to a stirred suspension of 2.5 g. of lithium alumishaken with ethyl acetate and aqueous sodium carbonate. num hydride in 400 ml. of anhydrous ethyl ether. After The organic layer is dried over magnesium sufate and heating the resulting mixture at reflux temperatures for then evaporated to dryness to yield 2-(2-aminoethyl)-3- ten hours the mixture is decomposed by careful addition (3,4-dichlorophenyl)-3-ethoxyphthalimi ineof water. The organic layer is dried over magnesium sul- The above prepared phthalimidihe (12 g.) is added in fate and evaporated to dryness to afford 2-(2-aminoethyl)- portions to a stirred suspension of 2.5 g. of lithium alumi- 5-ethylamino-1-phenylisoindoline. num hydride in 350 ml. of anhydrous ether. After reflux- In the same manner, the following compounds are ing the resulting mixture for ten hours, the mixture is prepared: decomposed by careful addition of water. The organic 5-arnino-2-(2-aminoethyl)-1-phenylisoindoline; layer is dried over magnesium sulfate and evaporated to 2-(Z-aminoethyl)-5,6-dichloro-l-phenylisoindoline; and dryness to afford 2-(2-aminoethyl) -1-(3,4-dichlorophenyl) 2-(2-aminoethyl) -5,6-dimethoxy-1-pheny1isoindoline. isoindoline. EXAMPLE 1 The above substitution reaction to convert 2-(2-aminoethyl)-3-(3,4-dichorophenyl) -3-hydroxyphthalimidine to the corresponding 3-chloro compound, is repeated utilizing phosphorus trichloride as the halogenating reagent.

The hydrochloride salts of the 2-(2-aminoethyl) isoindolines of this invention are prepared by admixing the particular 2-(Z-aminoethyl)isoindoline in an ethanolether solution of hydrogen chloride and, thereafter, sep- EXAMPLE VI arating the resulting hydrochloride salt. Other acid addition salts of the 2. (2-aminoethyl) R p the Procedure of EXamllles I the isoindolines described in the above examples are prepared lowing 2-(2-am1noe thyl)-3-hydroxyphthalrmrdmes are by similar procedures employing hydrobromic acid, hyconverted to h heremafter llsted yD droiodic acid, phosphoric acid, tartaric acid, acetic acid, dolmes: succinic acid, maleic acid and gluconic acid.

Starting material Product 2-(Q-aminoethyl)-3-(4-trifluorornethylphenyl)-3-hvdroxyphthalimidine .z-(z-arninoetliyl)-1-(4-trifluorornethylphenyl)isoindoline. 2-(Z-ammoethyl)-3-(4-bromopheny1)ai-hydroxyphthahmldine 2-(2-aminoethyl)-1-(4-bron1ophenyl)isoindoline.

2-(2-aminoethyl)-3-hydroxy-3-('5,6,7,8-tetrahydro-2-naphthyl) phthalimidina. 2-(2-aminoethyl)-3-furyl-3hydroxyphthalirnidine r 2-(2'arninoethyl)-3-henzyl-6-ethyl-3-hydroxyphthalimidine. 2-(2-aniinoethyl) -3-hydr0xy-3'pyridylphthalimidine 2-(2-aminoethyl) -3-hydroxy-3-(2thienyl)phthalimidine.

. 2-(2aminoethyl) -l-(5,6,7,8-tetrahydr0-2-naphthyl) isoindoline.

2-(2-arninoethyl)lfurylisoindoline.

2-(2-aminoethyl)-1-benzvl-fi-ethylisoindoline.

. 2-(Z-aminoethyl)-l-pyridylisoindoline.

2-(2-arninoethyl)-1-(2-thienyl)-is0indoline.

2 -(2-aminoethyl)-3-hydroxy-3-(3,4-dirnethoxyphenyl) phthalirmdme 2-(2-aminoethyl) -1(3,4-dimethoxyphenyl)isoindoline.

EXAMPLE VII What is claimed is: Forty grams of 2 (2 amin0ethy1) 6 chloro 3 hydroxy 1. A process for the production of compounds having 3-phenylphthalimidine and 25 ml. of thionylchloride are the formula:

heated to 35 C. for one hour. Thereafter, the reaction R2 mixture is evaporated to dryness to afford 2-(2-aminoethyl) -3,6-dichloro-3-phenylphthalimidine. N C H26 HZNHZ The above prepared 2-(2-aminoethyl)-3, 6-dichloro-3- phenylphthalimidine is admixed with butanol (25 ml.) R and the mixture is refluxed for one hour. Subsequently, 1 the reaction mixture is evaporated to dryness and the resi- Wherelh 1 18 Selected f om the group consrsting of hydrodue shaken with toluene and aqueous potassium carbonh yh Phenyl, P u l y mohohah? ate. The organic layer is dried over magnesium sulfate P y dlhalophehyl; fl fl y p y i and then evaporated to dryness to yield 2-(2-aminoethyl)- fl y p ny fi y p y monoflower) 3 butoxy-6 chloro 3 pheny1phtha1imidine alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl,

The above prepared phthalimidine (25 g.) is added in furyl and e h y p y R2 is seleeted from h portions to a stirred suspension of 5 g. lithium aluminum groupeohslshhg of hydrogen, halogen, ammo, lower hydride in 700 ml. of anhydrous diethylene glycol dikylamlhor lower alkyl and lower alkoxy; and 3 15 y methyl ether. After heating the resulting mixture for geh When 2 and s are dissimilar and when 2 and s twenty hours at 35 C., the mixture is decomposed by f f Same y are both Selected from the group 6011' careful addition of water. The organic layer is dried over slstlhg Y halogen, lower alkyl and lower magnesium sulfate and evaporated to dryness to afford Y; whleh comPTlSes reacting a y- Z-(Z-aminoethyl)-5-chloro-1-phenylisoindoline. ethynphthahmidihe 0f the formula! In the same manner, 2-(2-aminoethyl)-3-hydroxy-5- O methyl-3-phenethylphthalimidine is converted to 2-(2- aminoethyl) -6-methyl- 1 -phenethylisoindoline.

-CHzCHzNHz EXAMPLE VIII Ten grams of 2 (2 aminoethyl) 6 ethylamino 3 R3/ I R4 hydroxy-3-phenylphthalirnidine and 12.5 ml. of thionyl R1 chloride are heated to reflux temperatures for one hour. wherein R R and R are defined as above and R is Thereafter, the reaction mixture is evaporated to dryness lower alkoxy, with lithium aluminum hydride in an anhydrous reaction-inert ether solvent at a temperature range from about 35 C. to about 110 C. for a period of about two to about twenty-four hours.

2. A process as described in claim 1 which is conducted in an anhydrous reaction-inert ether solvent which is ethyl ether at about reflux temperature of the reaction mixture for a period of about seventeen hours.

3. A process as described in claim 1 for the production of: 2- (Z-aminoethyl) -1- (4-chlorophenyl) isoindoline.

4. A process as described in claim 1 for the production of 2-(2-aminoethyl)-l-(4-chlorophenyl)isoindoline which comprises the hydrogenolysis of 2-(2-aminoethyl)- 3-(4-chlorophenyl)-3-ethoxyphthalimidine with lithium aluminum hydride, in ethyl ether at about the reflux temperature of the reaction mixture for about seventeen hours.

5. A process for the production of compounds of the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, phenyl, phen(lower) alkyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di- (lower)alkyphenyl, trifluoromethylphenyl, mono(lower) alkoxyphenyl, di(lower)alkoxyphenyl, thienyl, pyridyl, furyl and tetrahydro-Z-Haphthyl; R is selected from the group consisting of hydrogen, halogen, amino, lower alkylamino, lower alkyl and lower alkoxy; and R is hydrogen when R and R are dissimilar and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; which comprises contacting a 2-(2-aminoethyl)-3- hydroxyphthalimidine of the formula:

wherein R R and R are defined as above, with a halogenating reagent selected from the group consisting of phosphorous trichloride, phosphorus tribromide, phosphorus pentachloride and thionyl chloride at a temperature range from about C. to about C. for a period of about one-half hour to about three hours, to form a 2-(2-aminoethyl)-3-halophthalimidine of the formula:

wherein R R and R are defined as above and R is selected from the group consisting of chloro and bromo, reacting said 2-(2-aminoethyl)-3-halophthalimidine with a lower alkanol at a temperature range from about 25 C. to about C. for a period of about one-half hour to about three hours, to form a 3-alkoxy-2-(2-aiminoethyl) phthalimidine of the formula:

wherein R R and R are defined as above, and R is lower alkoxy; and reacting said 3-alkoxy-2-(2-aminoethyl) phthalimidine with lithium aluminum hydride in an anhydrous reaction-inert ether solvent at a temperature range from about 35 C. to about C. for a period of about two to about twenty-four hours.

6. A process as described in claim 5 for the production of: 2- Z-aminoethyl) -1- (4-chlorophenyl) isoindoline.

7. A process as described in claim 5 for the production of 2-(2-aminoethyl)-1-(4-chlorophenyl)isoindoline which comprises:

(a) reacting 2-(2-aminoethyl)-3-(4-chlorophenyl)-3- hydroxyphthalirnidine with thionyl chloride at about the reflux temperature of the reaction mixture for a period of about one hour to afford Z-(Z-aminoethyl) -3 -chloro-3- (4-chlorophenyl phthalimidine;

reaching said Z-(Z-aminoethyl)-3-chloro-3-(4-chlorophenyl)phthalirnidine with ethanol at about the reflux temperature of the reaction mixture for about one hour to aiford Z-(Z-aminoethyl)-3-(4-chlorophenyl)-3-ethoxyphthalimidine; and (c) reacting said 2-(2-aminoethyl)-3-(4-chlorophenyl) 3-ethoxyphthalimidine with lithium aluminum hydried in ethyl ether at about reflux temperature of the reaction mixture for about seventeen hours.

References Cited UNITED STATES PATENTS 3,334,113 8/1967 Houlihan 260-309.7

ALEX MAZEL, Primary Examiner J. A. NARCAVAGE, Assistant Examiner US. Cl. X.R. 

